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Integrating Pharmacogenomic Questions Into GCIG Ovarian Cancer Clinical Trials. Lori Minasian, MD Chief, Community Oncology and Prevention Trials Research Group, Division of Cancer Prevention, NCI, NIH, HHS. Definition. Pharmacogenomics (PGx)

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Integrating pharmacogenomic questions into gcig ovarian cancer clinical trials

Integrating Pharmacogenomic Questions Into GCIG Ovarian Cancer Clinical Trials

Lori Minasian, MD

Chief, Community Oncology and Prevention Trials Research Group, Division of Cancer Prevention, NCI, NIH, HHS


Definition
Definition Cancer Clinical Trials

  • Pharmacogenomics (PGx)

    • Influence of Individual Genomic Polymorphisms on Drug Response

  • Personalized Medicine

    • Identify Risk for Toxicities

    • Identify Predictive Markers of Efficacy


Pharmacogenomics in drug development

Safety Cancer Clinical Trials ‘Pgx for Individual’

Efficacy‘Pgx for Group’

Increased risk of serious adverse event

Predict

increased response

Using genes

to predict

response

to medicines

No increased risk of serious adverse event

Predict

reduced response

Pharmacogenomics in Drug Development


Context
Context Cancer Clinical Trials

  • Rising concern about safety

    • media reports, Congress, IOM

  • HHS Recommendations 2008

    • Enhanced Research in PGx

    • Enhanced Research on Clinical Decision Making Tools, esp PGx

    • Direct Agencies to Work with Stakeholders to Enhance incorporation of PGx findings into routine healthcare delivery


Context1
Context Cancer Clinical Trials

  • Rapid Increase in Newly Approved Drugs and Biologics

  • Increasing New Approvals Including PGx Language in Labeling Indication


Currently approved oncology drugs
Currently Approved Oncology Drugs Cancer Clinical Trials



Pharmacogenomics tailoring cancer treatment
Pharmacogenomics: Cancer Clinical Trials Tailoring Cancer Treatment

  • Identify specific epidemiologic, clinical and genetic profiles that could enhance optimal response to cancer therapy and minimize toxicity

  • Selected examples:

    • Irinotecan and UGT1A1 gene for CRC

    • 6-MP and TMPT gene for ALL

    • Tamoxifen and CYP2D6 for BC


Wild-type Cancer Clinical Trials

Mutant

Free of hematologic toxicity (Probability)

Irinotecan and UGT1A1

Cote, JF et al. UGT1A1 polymorphism can predict hematologic toxicity in patients treated with irinotecan. Clin Cancer Res 2007;13:3269-3275


Pharmacogenomics in ovarian cancer review by paige brown 2009
Pharmacogenomics in Ovarian Cancer Cancer Clinical Trials(Review by Paige & Brown 2009)

  • Drug Response:

    • Transport (ABCB1)

    • Metabolism (P450, GST)

    • DNA Repair (ERCC1)

    • Markers of Tumor Response (eg p53)


Pharmacogenomics in scottish rt ovarian cancer march 2007
Pharmacogenomics in Scottish RT Ovarian Cancer Cancer Clinical Trials(March 2007)

  • Pts randomized to

    • Docetaxel + Carboplatin vs

    • Paclitaxel + Carboplatin

  • Germline DNA from whole blood on 914 or 1077 patients

  • Genotyping for 27 polymorphisms in 16 genes

  • No clear candidates for taxane/platinum PGx markers found


Pharmacogenomics
Pharmacogenomics Cancer Clinical Trials

  • Better understanding of regulation of chemotherapy mechanisms of action

  • Need large collections of well annotated specimens in conjunction with clinical trials

    • NCI moving towards collecting blood on patients in phase III trials

    • GCIC offers the possibility of looking at PGx specific to ethnic populations, esp if achieve goal of common control arms on phase III trials


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